title: Cyclin G1 expands liver tumor-initiating cells by Sox2 induction via Akt/mTOR signaling.
abstract: Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients.
authors.affiliation: Corresponding Authors: Hong-Yang Wang, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/Institute, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China. hywangk@vip.sina.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Shu-Zhen
authors.initials: SZ
authors.lastname: Chen
authors.forename: Dai-Min
authors.initials: DM
authors.lastname: Xiang
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Dan
authors.initials: D
authors.lastname: Cao
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D056766:Cyclin G1 / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; D056766:Cyclin G1; D010671:Phenylurea Compounds; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D009536:Niacinamide; D000077157:Sorafenib; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin